Since 1989, we have led the ascertainment,evaluation, and genetic analysesof the NIMH GeneticsInitiative Alzheimer's disease (AD) sample. This set of AD families, which currently includes 457 families, is the argest uniformly ascertained and evaluated sample assembled for the study of AD genetics. Over the first ive years of this R37, we have continued to carry out genetic analysesand follow-up studies of our a high- resolution whole genome genetic linkage screen for novel AD candidate genes. We have focused on linkage peaks identified on chromosomes 9 and 10, and identified late-onsetAD candidate genes in both ofthese inkage peaks: insulin degrading enzyme (IDE; 10q) and ubiquilin 1 (UBQLN1; 9q). In addition tofunctionally characterizing these genes for potential pathogenic effects in AD, we have built a highly efficient gene discovery pipeline, customized for large-scale generation, confirmation, storage and analysis of SNP genotype information. Our NIMH family-based association database of positional candidate gene contains over 500,000 genotypes for more than 300 SNPs in over 150 genestested in the full NIMH sample. Furthermore, we have recently obtained nearly one billion genotypes for the NIMH sample from a high- density, whole genome association screen using the Affymetrix 500K SNPchip, currently under analysis. By early October, we will also have obtained the results of a screen of the Affymetrix20,000 coding region SNPs (cSNPs) for the entire NIMH AD family sample. This screen should identify SNPs with a higher probability of potentially pathologenic effects.These combined data sets now provide anunprecedented array of AD candidate genes collectively accounting for as much as 95% of the genetic van'ability of AD. In the second half of this R37, we will carry out confirmatory and follow-up studies of these AD candidate genes. First, SNPs exhibiting family-basedassociation with AD will be confirmed by manual genotyping. Second, they will be confirmed in additional AD family-based samples. Third, tagging SNPs for all inkage disequilibrium blocks in confirmed candidate genes will be tested in the NIMH and confirmatory samples. Fourth, bioinformatic analyses and resequencing will be performed to identify potentially pathogenic mutations and gene variants. The strongest candidate genes will then be validated in a wide array of functional analyses to assess the potential pathogenicity of AD-associatedgene variants.